Atherosclerosis is the result of pathological processes that develop over many years, and therefore any successful treatment must last for decades. Apolipoprotein E (apoE) is a plasma protein implicated in cardiovascular diseases and its anti-atherogenic properties have been reported. Previous studies of experimental apoE gene therapy for mouse models of dyslipidemia found the effectiveness of the approach. However, in these studies using early generation adenoviral vectors, the effects terminated prematurely because the transgene expression was short-lived after delivery of these vectors. We have recently shown the effectiveness of helper-dependent adenovirus (HDAd) mediated gene transfer. A single injection of HDAd containing the apoE gene expressed apoE at the normal levels for at least 2.3 years without significant hepatotoxicity in apoE -/- mice (Kim et al., Proc. Natl. Acad. Sci. USA 98:13282-13287, 2001). We also reported the strategy to re-stimulate transgene expression by readministration of the same vector of a different serotype. In this proposal, we will use HDAd vector to express human apoE3 gene, and test the hypothesis that anti-atherogenic properties of apoE contribute to inhibition of atherosclerotic lesion progression (a retardation of an increase of lesion size) and remodel arterial walls (a change of structural composition), but concomitant prolonged normalization of plasma lipid is necessary to induce lesion regression (a reduction of lesion size). We propose 4 specific aims: (1) to investigate the anti-atherogenic properties of apoE by hepatic apoE expression in apoE -/- mice and in LDL receptor deficient (LDLR -/-) mice; (2) to examine if prolonged normalization of plasma lipid in LDLR -/- mice by co-expression of VLDL receptor further contribute to the protection against atherosclerosis; (3) to test if apoE gene therapy induces a host immune response to apoE in various mouse strains and to develop a strategy to evade any host immune responses; and (4) to examine if shielding the HDAd vector from the innate immune system increases in vivo transduction efficiency with a reduction of the toxicity of HDAd vectors.